Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter.
Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 35
3
An Integrated National System
for Addressing Foreign Animal
Diseases and Zoonotic Diseases
US federal agencies have a responsibility for and a vital role in the preven-
tion, detection, and control of foreign animal diseases (FADs) and zoonotic dis-
eases that have the potential for broad health and socioeconomic effects. His-
torically, the US Department of Agriculture (USDA) has addressed disease
threats to the agricultural animal industries that may occur as a result of intro-
duction of an FAD, and confronting the potential human health effects of zoono-
tic diseases has been the responsibility of the Department of Health and Human
Services. Although the historical mandates of those agencies have not changed,
the disease threats have. The threat of bioterrorism, heightened after the events
of September 11, 2001; the later creation of the Department of Homeland Secu-
rity (DHS); and advances in biotechnology that have increased the risk of pur-
poseful or inadvertent modifications of microorganisms that could increase viru-
lence, expand host range, or enhance transmissibility (Berns et al., 2012;
Enserink and Cohen, 2012) have drawn the world’s attention to the threat of
disease outbreaks. Our growing global interconnectivity; the growing global
population; the demand for food, particularly animal-based protein; and increas-
ing contact with wild ecosystems through land development make it likely that
emerging and re-emerging pathogens will continue to occur and spread at an
even greater rate. Scientists predict that two to four new pathogens will emerge
each year and that RNA viruses, especially those at the human-animal interface,
will present the greatest threat (Brownlie et al., 2006). The factors that could
create “the perfect microbial storm”, as described by the Institute of Medicine
(IOM, 2003), are still in place and intensifying, and this suggests that the risk of
disease incursion continues to increase and that the implications are even more
profound. The impact of those factors has been felt on local to global levels, and
has resulted in policy changes in disease reporting by such international agen-
cies as the World Health Organization (WHO) through the codification of the
35
OCR for page 36
36 CRITICAL LABORATORY NEEDS FOR ANIMAL AGRICULTURE
International Health Regulations in 2005 (WHO, 2007) and the revised list of
notifiable diseases (see Table 2-1 in Chapter 2) and requirements for notification
of emerging diseases by the World Organisation for Animal Health (OIE, 2010).
Commensurate with those changes is an expectation that WHO and OIE mem-
ber countries will have a reliable infrastructure for disease surveillance and re-
sponse (Fidler, 2005; Baker and Fidler, 2006).
As noted in Chapter 2, a number of previous National Research Council
(NRC) and IOM studies have addressed current threats to our nation’s health
and welfare, including both FADs and zoonotic diseases (IOM, 2003). A recent
IOM and NRC report, Sustaining Global Surveillance and Response to Emerg-
ing Zoonotic Diseases (2009), is of particular relevance and recommended sev-
eral actions to strengthen the global capacity for addressing disease threats. The
recommendations included improved use of information technology (Recom-
mendation 1-2), a strengthened global laboratory network (Recommendation 1-
3), and expanded human-resource capacity (Recommendation 1-4) to support
disease surveillance and response (IOM and NRC, 2009). The recommendations
for a global system apply equally to the framework for animal-disease surveil-
lance and response within the United States, whether for zoonotic diseases or
FADs. Protecting US animal agriculture requires a well-integrated system that
spans authorities, geography, and many programs and activities. The idea that a
chain is only as strong as its weakest link applies to the complex systems needed
to protect animal agriculture from the incursion of serious diseases and to ad-
dress a riskier world.
THE ROLE OF A NATIONAL LABORATORY
FACILITY IN AN INTEGRATED SYSTEM
Critical Core Functions
The committee considered its task in the context of an integrated system in
the United States for addressing FAD and zoonotic disease threats and the role
of a national biocontainment laboratory in such a system. The ideal system
would capture and integrate the substantial human and physical assets distrib-
uted throughout the nation to optimally address the threat of FADs and zoonotic
diseases. It would include surveillance and detection, diagnostics, and disease
response and recovery and would have research and development and training of
the workforce as critical core elements to support each of these functional arms
(see Figure 3-1). These elements would provide the capabilities needed to sup-
port multiple disease-control strategies, the choice of which is dependent on
many factors such the likelihood of introduction to the United States, disease
spread rates, and cost and effectiveness of control. A robust laboratory infra-
structure underlies all those components. A national role in the coordination of
the system is essential, and a federal laboratory or network of laboratories would
be the cornerstone of the system. The ideal system would reach beyond our bor-
ders to tap the expertise and resources of the global infectious-disease surveil-
OCR for page 37
AN INTEGRATED NATIONAL SYSTEM FOR ADDRESSING DISEASES 37
lance, diagnostic, and research communities. Recognizing the threat posed by
zoonotic diseases and the known and potential roles of animals in maintaining
and transmitting infectious agents, the ideal system would capture both human-
and animal-health expertise and laboratory infrastructure to achieve the common
goals of disease recognition and response.
T rained Workforce
Integrated
System for
Disease Threats
Diagnostic
Laboratory Network
FIGURE 3-1 Components of an integrated national system for addressing foreign animal
disease and zoonotic disease threats. Laboratory infrastructure underlies all components.
Surveillance
At the heart of early recognition of a newly introduced disease, whether its
occurrence is intentional or natural, is the ability to gather and access data from
the field. Technology for capturing the billions of bits of information flowing
through electronic channels every day can help to detect unusual events in real
time, but it is unlikely that a technology-based approach to data acquisition will
ever be the sole or most accurate means by which we can recognize a disease
occurrence in the United States. Human resources and a trained workforce are
vital to early recognition and verification of an emerging disease event. It is es-
sential to ensure that trained personnel, both professional and lay, are well
versed in the manifestations of known diseases in animals and humans and at-
tuned to the variations in disease expression that can indicate a newly emerging
disease event. The various clinical signs and pathological changes caused by
FAD and zoonotic disease agents can be demonstrated effectively with experi-
mental inoculation of animals, and many FAD and zoonotic disease agents re-
quire animal biosafety level 3 (ABSL-3), biosafety level 3 agriculture (BSL-
3Ag), or ABSL-4 containment for live-animal work; so training of the work-
force in early detection is an essential function that should be provided by a cen-
OCR for page 38
38 CRITICAL LABORATORY NEEDS FOR ANIMAL AGRICULTURE
tral laboratory that has appropriate biocontainment (see Box 3-1 for the descrip-
tion of biosafety levels). The committee agreed that the strategic use of video
imaging, plastination (fixation, dehydration, impregnation, and hardening of
tissues), and other technological means to capture and broadly disseminate train-
ing materials through electronic media, and engagement of the workforce in
disease-control campaigns in regions that are endemic for animal diseases or
that experience outbreaks of diseases foreign to the United States could reduce
the need for hands-on training with experimentally infected animals and thereby
reduce the need for training space in the proposed NBAF.
BOX 3-1
Laboratory Biosafety Levels and Types of Pathogens Handled at Each Level
as defined in The Biosafety in Microbiological and
Biomedical Laboratories, 5th Edition
Biosafety Level 1 (BSL-1): Biosafety Level 1 is suitable for work involving
well-characterized agents not known to consistently cause disease in immunocompe-
tent adult humans, and present minimal potential hazard to laboratory personnel and
the environment.
Biosafety Level 2 (BSL-2): Biosafety Level 2 builds upon BSL-1. BSL-2 is
suitable for work involving agents that pose moderate hazards to personnel and the
environment. It differs from BSL-1 in that: 1) laboratory personnel have specific
training in handling pathogenic agents and are supervised by scientists competent in
handling infectious agents and associated procedures; 2) access to the laboratory is
restricted when work is being conducted; and 3) all procedures in which infectious
aerosols or splashes may be created are conducted in biosafety cabinets or other
physical containment equipment.
Biosafety Level 3 (BSL-3): Biosafety Level 3 is applicable to clinical, diagnos-
tic, teaching, research, or production facilities where work is performed with indige-
nous or exotic agents that may cause serious or potentially lethal disease through the
inhalation route of exposure.
Animal Biosafety Level 3 (ABSL-3): Animal Biosafety Level 3 involves prac-
tices suitable for work with laboratory animals infected with indigenous or exotic
agents, agents that present a potential for aerosol transmission, and agents causing se-
rious or potentially lethal disease.
Biosafety Level 3 Enhanced (BSL-3E): Situations may arise for which en-
hancements to BSL-3 practices and equipment are required; for example, when a
BSL-3 laboratory performs diagnostic testing on specimens from patients with hem-
orrhagic fevers thought to be due to dengue or yellow fever viruses. When the origin
of these specimens is Africa, the Middle East, or South America, such specimens
might contain etiologic agents, such as arenaviruses, filoviruses, or other viruses that
are usually manipulated in a BSL-4 laboratory. Examples of enhancements to BSL-3
laboratories might include: 1) enhanced respiratory protection of personnel against
aerosols; 2) high-efficiency particulate air filtration of dedicated exhaust air from the
laboratory; and 3) personal body shower.
(Continued)
OCR for page 39
AN INTEGRATED NATIONAL SYSTEM FOR ADDRESSING DISEASES 39
Box 3-1 Continued
Biosafety Level 3 Agriculture (BSL-3Ag): In agriculture, special biocontain-
ment features are required for certain types of research involving high consequence
livestock pathogens in animal species or other research where the room provides the
primary containment. To support such research, the US Department of Agriculture
has developed a special facility designed, constructed and operated at a unique ani-
mal containment level called BSL-3Ag. Using the containment features of the stan-
dard ABSL-3 facility as a starting point, BSL-3Ag facilities are specifically designed
to protect the environment by including almost all of the features ordinarily used for
BSL-4 facilities as enhancements.
Biosafety Level 4 (BSL-4)1: Biosafety Level 4 is required for work with dan-
gerous and exotic agents that pose a high individual risk of aerosol-transmitted labo-
ratory infections and life-threatening disease that is frequently fatal, for which there
are no vaccines or treatments, or a related agent with unknown risk of transmission.
Agents with a close or identical antigenic relationship to agents requiring BSL-4 con-
tainment must be handled at this level until sufficient data are obtained either to con-
firm continued work at this level, or re-designate the level.
SOURCE: CDC (2009).
Training at a national facility can be supplemented, for example, with
USDA Animal and Plant Health Inspection Service (APHIS) online re-
sources.2
The online FAD information and Emerging and Exotic Diseases of
Animals (EEDA) course provided by the Center for Food Security and
Public Health at Iowa State University.3
The Foreign Animal Disease Training Course at Colorado State Uni-
versity.4
The Foreign Animal, Emerging Diseases course at the University of
Tennessee College of Veterinary Medicine.5
1
The designation “ABSL-4 large animal” is a terminology used by DHS to specify ar-
eas where biosafety level 4 research in large animals is conducted, but this term has not
been codified by the BMBL.
2
URL: http://www.aphis.usda.gov/emergency_response/NAHEM_training/index_nahem.s
html (accessed June 1, 2012).
3
URL: http://www.cfsph.iastate.edu/EEDA-Course/ (accessed June 1, 2012). The EEDA
Web-based course was developed in 2000-2002 by Iowa State University, the University
of Georgia, the University of California, Davis, and USDA. It has been used since 2002
in US veterinary schools to raise awareness of foreign, emerging, and exotic animal dis-
eases and the appropriate responses if an unusual disease is suspected. The EEDA book is
provided to all students at veterinary colleges and schools in the United States through
funding from APHIS.
4
URL: http://www.cvmbs.colostate.edu/aphi/ (accessed June 5, 2012).
OCR for page 40
40 CRITICAL LABORATORY NEEDS FOR ANIMAL AGRICULTURE
Continuing-education courses, such as Response to Emergency Animal
Diseases in Wildlife,6 and other online and digital media sources of
FAD information (such as a CD on FADs provided by the National
Center for Animal Health Emergency Management).7
Core or elective courses in FADs that are required to be in the curricula
of the 28 accredited colleges and schools of veterinary medicine in
North America.
Specialized courses in FAD recognition, such as the Smith-Kilborne
FAD course offered at the Cornell University College of Veterinary
Medicine and Plum Island Animal Disease Center (PIADC).8
Box 3-2 summarizes current FAD courses offered at PIADC.
BOX 3-2
Training Courses Offered at the Plum Island Animal Disease Center
Foreign Animal Disease Diagnostics Course
The regular Foreign Animal Disease Diagnostics (FADD) course is intended to
train veterinarians employed by federal agencies (mostly USDA-APHIS Veterinary
Services), by states, and by the military (primarily the Army Veterinary Corps). The
FADD training course is provided three times a year with a maximum participation of
30 veterinarians each time. Today, federal, state, and military veterinarians take the
same course (the military Transboundary Animal Diseases (TAD) course was separate
for several years). The course includes live experimental animal demonstrations of 11
important livestock diseases (such as foot-and-mouth disease, classical swine fever,
exotic Newcastle disease, and highly pathogenic avian influenza) and lectures on 23
diseases of livestock and poultry species. It also covers lectures and demonstrations on
the use of personal protective equipment; on-farm disease investigation; collection,
packaging, and mailing of diagnostic samples; and administrative procedures related to
disease investigation, reporting, and emergency response.
Veterinary Laboratory Diagnostician Course
A separate 1-week course is offered to faculty and residents of US veterinary col-
leges and schools each year. It follows the same format as the FADD course. Partici-
pants do not spend much time in USDA-APHIS administrative training, and they do not
become FAD diagnosticians.
(Continued)
5
URL: http://www.veterinarypracticenews.com/vet-breaking-news/foreign-animal-em
erging-disease-course.aspx (accessed June 6, 2012).
6
URL: http://www.aphis.usda.gov/animal_health/prof_development/ (accessed June 4,
2012).
7
Jon Zack, USDA-APHIS, pers. comm., June 1, 2012.
8
URL: http://www.aphis.usda.gov/animal_health/prof_development/smith_kilborne.shtml
(accessed May 31, 2012).
OCR for page 41
AN INTEGRATED NATIONAL SYSTEM FOR ADDRESSING DISEASES 41
BOX 3-2 Continued
International Transboundary Animal Diseases Course
The International Transboundary Animal Disease (ITAD) course is organized and
funded through USDA-APHIS International Services (in contrast with the above
courses, which are organized and funded through USDA-APHIS Veterinary Services).
The course has been given 11 times, once almost every year, with up to 30 international
veterinarians each time. It has been delivered completely in Spanish six times. Partici-
pants are selected by veterinary and agricultural attachés from among government or
academic veterinarians around the world. As in the case of the FADD and the Veterinary
Laboratory Diagnostician courses, there is no fee to attend this course; the participants’
sponsoring institutions pay for associated travel, lodging, and meals. The ITAD course
follows the same schedule and animal demonstrations as the regular FADD course, ex-
cept that participants do not spend time on USDA-APHIS administrative policies and
procedures; instead, they are exposed to discussion on international trade, epidemiology,
and emergency response.
Smith-Kilborne Foreign Animal Disease Course
This course in the current format has been delivered for 10 years and includes one
veterinary student (after completion of their second year) from each of the 28 US col-
leges and two international veterinary students (from Canada or Mexico). The Smith-
Kilborne program is designed to acquaint veterinary students with various FADs that
potentially threaten our domestic animal population. The course includes classroom
presentations for 3 days at Cornell University College of Veterinary Medicine on dis-
eases and their implications and 2 days of laboratory experience at the PIADC, where
participants observe foot-and-mouth disease, African horse sickness, highly pathogenic
avian influenza, and exotic Newcastle disease. The PIADC portion of the course coin-
cides with the first week of a regular FADD course, and experimentally infected animals
are shared by the two courses. Students practice necropsies on poultry only. After the
course, students are expected to share their new knowledge by giving seminars at their
colleges.
Apart from the need to maintain a trained and ready workforce and a poten-
tial research and development requirement to support this component, field-
based surveillance itself does not require high-biocontainment (BSL-3 and BSL-
4) space, although case or outbreak investigations of zoonoses may require use
of appropriate personal protective equipment (PPE).
Diagnostics
Historically, the National Veterinary Services Laboratories (NVSL) at
Ames, Iowa have provided support for diagnosis of endemic “program dis-
eases”9 in the United States by qualified and approved nonfederal laboratories.
Training programs for laboratory personnel, proficiency testing, and reference
9
Program diseases are those designated as “necessary to bring under control or eradi-
cate from the United States” (APHIS, 2012).
OCR for page 42
42 CRITICAL LABORATORY NEEDS FOR ANIMAL AGRICULTURE
reagents have been valuable contributions to state laboratories’ ability to per-
form diagnostic testing for control programs targeting such endemic diseases as
brucellosis, pseudorabies, tuberculosis, and equine infectious anemia. The role
of the NVSL Foreign Animal Disease Diagnostic Laboratory (FADDL), which
is co-located with USDA-ARS and DHS at the PIADC, has been more limited in
that it has focused on FADs, for which nonfederal laboratories were not allowed
to perform diagnostic testing. The development of the National Animal Health
Laboratory Network (NAHLN) in 2002 and associated changes in policy
(Memorandum 580.4)10 now allow state laboratories to conduct diagnostic test-
ing for FADs. Box 3-3 provides an overview of the NAHLN from its inception
to the present.
The NAHLN is an excellent example of an integrated system that was cre-
ated to address the nation’s needs, in this case for diagnostic support for early
detection, response to an outbreak, and recovery. With the implementation of the
NAHLN, the NVSL laboratories at the National Centers for Animal Health
(NCAH) in Ames, Iowa, and FADDL at Plum Island now play a vital and irre-
placeable role in supporting testing for FADs in approved NAHLN laboratories.
Initial test validation (including analytical assessment with samples collected
from experimentally infected animals, diagnostic sensitivity, and specificity
determination with samples obtained from outbreaks in endemic areas outside
the United States, which can be handled only at PIADC and NCAH), reference-
reagent production, and proficiency testing are all examples of the critical core
functions best managed by a federal laboratory in support of diagnostic testing
on a nationwide basis in qualified laboratories. Continued assessment of vali-
dated assays against newly arising variants obtained from outbreaks outside the
United States also requires adequate biocontainment. For foot-and-mouth dis-
ease, this is performed in a federal facility approved for handling of foot-and-
mouth disease virus (FMDv) .
Finally, the role of NVSL in confirmatory diagnosis of the index case of an
FAD cannot be overvalued. Because of the inevitable effects on lives and liveli-
hoods, the index case of a new disease in the United States must be officially
reported by a federal agency. The current role of state NAHLN laboratories in
the diagnosis of an index case of a potential FAD is to obtain a test result that is
actionable but presumptive; appropriate samples are also sent to NVSL, Ames or
Plum Island for confirmation. Assays such as cell culture used for confirmatory
diagnosis result in amplification of a virus that may be highly contagious and
requires a modern, high-biocontainment laboratory environment like that pro-
posed for the NBAF. The ability to culture live FAD pathogens like FMDv for
characterization and reference is a critical core function of a national biocon-
tainment laboratory.
10
URL: http://www.aphis.usda.gov/animal_health/lab_info_services/downloads/VSMe
mo580_4.pdf (accessed May 31, 2012).
OCR for page 43
AN INTEGRATED NATIONAL SYSTEM FOR ADDRESSING DISEASES 43
BOX 3-3
The National Animal Health Laboratory Network
The National Animal Health Laboratory Network (NAHLN), launched in 2002,
is a cooperative effort of the US Department of Agriculture (USDA) Animal and
Plant Health Inspection Service, the USDA National Institute of Food and Agricul-
ture, and the American Association of Veterinary Laboratory Diagnosticians
(AAVLD). The mission of the NAHLN is to provide accessible, timely, accurate, and
consistent animal disease diagnostic services nationwide that meet the epidemiologi-
cal and disease reporting needs of the country. The NAHLN also maintains the capac-
ity and capability to provide laboratory services in the event of an FAD or emerging
disease event in the country. The NAHLN focuses on diseases of livestock, but it also
responds to disease events in nonlivestock species. The NAHLN has contributed to
several surveillance activities and control strategies of national interest. The NAHLN
laboratories are the first line of early detection of transboundary diseases and serious
zoonotic diseases introduced into the United States.
The origins of the NAHLN are in the Public Health Security and Bioterrorism
Preparedness and Response Act of 2002 and Homeland Security Presidential Direc-
tive 9 (HSPD-9), both of which called on USDA to establish surveillance systems for
animal diseases that would mitigate threats to the nation’s agricultural sector.
The USDA Safeguarding Review (NASDARF, 2001) identified the need for a
network that would coordinate laboratory capacity at the federal level with the exten-
sive infrastructure of the state and university animal disease diagnostic laboratories.
Cooperative agreements were awarded by USDA in May 2002 to 12 state and univer-
sity diagnostic laboratories for a 2-year period. The NAHLN has grown to 58 labora-
tories (53 state and five federal) in 40 states (see Figure 3-2), and the capability and
capacity of the nation’s animal-disease surveillance program have grown with it.
At the federal level, USDA’s National Veterinary Services Laboratory (NVSL)
laboratory units in Ames, Iowa, and Plum Island, New York (Foreign Animal Disease
Diagnostic Laboratory [FADDL]), serve as the national reference and confirmatory
laboratory for veterinary diagnostics, and it coordinates the training, proficiency test-
ing, assistance, and prototypes for diagnostic tests that are used in the state NAHLN
laboratories. One component of NVSL’s contribution to the NAHLN is a “train the
trainer” program that has increased the number of personnel in NAHLN laboratories
who can perform tests for the diagnosis of FADs. The program, offered at FADDL
and NVSL, Ames is an example of the successful collaboration between the NVSL
and NAHLN laboratories that has resulted in a national network of laboratory person-
nel who are trained to perform tests for FADs—a resource that did not exist before
the NAHLN.
The state and university animal-disease diagnostic laboratories in the NAHLN
perform routine diagnostic tests for endemic animal diseases, and they have received
specific approval to perform tests for FADs as a part of the national surveillance
strategy. A current example of the NAHLN’s value is the diagnosis of the fourth US
case of bovine spongiform encephalopathy (BSE), reported by USDA on April 24,
2012. A sample collected from a dairy cow was submitted to the California Animal
Health and Food Safety (CAHFS) laboratory at the University of California at Davis,
(Continued)
OCR for page 44
44 CRITICAL LABORATORY NEEDS FOR ANIMAL AGRICULTURE
BOX 3-3 Continued
an NAHLN laboratory that performs BSE testing through a contractual agreement with
USDA. When the CAHFS laboratory determined that the sample was positive, suspect, or
inconclusive for BSE, it was sent to the NVSL for confirmation. That procedure is rou-
tine and conforms with the established protocol outlined in a Veterinary Services memo-
randum (VS Memorandum 580.4). Thousands of BSE tests have been performed in
NAHLN laboratories in support of USDA’s BSE surveillance strategy. Similar testing
agreements for a wide array of animal diseases—including foot-and-mouth disease, clas-
sical swine fever, avian influenza, exotic Newcastle disease, chronic wasting disease and
scrapie, swine influenza, pseudorabies, and vesicular stomatitis—have been established
with NAHLN laboratories nationwide.
The NAHLN effectively demonstrates the value of collaboration between the federal
government and state and university animal-disease diagnostic laboratories and may
serve as a template for a new relationship among the Department of Homeland Security,
USDA, and the NAHLN. Such a new collaboration could accomplish some of the tasks
of the proposed National Bio- and Agro-Defense Facility (NBAF) by using infrastructure
that already exists in the state and university veterinary diagnostic network, including
facilities, professional expertise, and support.
FIGURE 3-2 National Animal Health Laboratory Network. SOURCE: USDA-APHIS
(2012).
SOURCE: USDA-APHIS (2012).
OCR for page 45
AN INTEGRATED NATIONAL SYSTEM FOR ADDRESSING DISEASES 45
Outbreak Response
If the United States identifies a known FAD or a newly emergent disease
within its borders, a rapid, comprehensive response is necessary. The type of
response will depend on the disease and on whether it is known or newly identi-
fied. The historical approach for control of an FAD outbreak has been to quaran-
tine infected premises with diagnostic screening in surrounding zones followed
by additional quarantine and diagnostic screening focused on new infected
premises with slaughter of infected animals. That approach requires that new
cases be rapidly identified with diagnostic assays that have a high level of diag-
nostic sensitivity and the capability of being performed in a high-throughput
manner, particularly in the case of rapidly spreading diseases, such as foot-and-
mouth disease. Technological advances in the last few decades have led to the
development of direct pathogen identification assays that have very high sensi-
tivity, that target and amplify nucleic acids, and that have the capability of high
throughput. The NAHLN has successfully deployed well-validated real-time
polymerase chain reaction (PCR) assays for detection of foot-and-mouth dis-
ease, avian influenza, pandemic H1N1 influenza, classical swine fever, African
swine fever, and rinderpest. That would not have been possible without the sup-
port of a federal laboratory: initial validation of the assays was conducted at
PIADC, where samples from experimentally inoculated animals were vital for
early analytical sensitivity testing. Continuing support for reference reagents,
proficiency testing, and ensuring that reagents are available in required quanti-
ties to respond to a disease outbreak is fundamental to being prepared and re-
sponsive during a real event. It is a function that can best be performed by a fed-
erally supported program that includes appropriate laboratory biocontainment.
The United States is increasingly incorporating vaccination into outbreak-
response plans for FADs. This scientifically sound and justifiable approach is
expected by a populace that increasingly respects the value and welfare of agri-
cultural animals beyond their place in the food chain. Vaccines would probably
be used strategically in “ring vaccination” to minimize the number of animals
that would need to be killed to control an outbreak. Vaccine development has
been going on at PIADC for many years, but as a result of the change in out-
break response and the acceptance of regionalization and compartmentalization
by OIE, a higher priority has been attached to vaccine development where gaps
exist, and the goal is to develop vaccines that allow differentiation of infected
from vaccinated animals (“DIVA” vaccines) and diagnostics. Research on vac-
cine development for FAD agents requires the ability to grow and manipulate an
agent, which in turn requires biocontainment at BSL-3, BSL-3Ag, BSL-3E lev-
els, and—for agents such as Hendra and Nipah viruses, hemorrhagic fever vi-
ruses, and some arboviruses—BSL-4 level. Equivalent ABSL containment is
required for live-animal work. It is important to note that all the viral agents that
require BSL-4 containment are zoonotic; that is, none of the livestock-specific
FADs require BSL-4 laboratory containment. Nevertheless, a disease outbreak
of a zoonotic virus that requires BSL-4 containment would require appropriate
OCR for page 56
56 CRITICAL LABORATORY NEEDS FOR ANIMAL AGRICULTURE
The National Institute of Allergy and Infectious Diseases, which is part of
NIH, supports 11 university-based laboratories designated as Regional Centers
of Excellence for Biodefense and Emerging Infectious Diseases (RCEs). The
RCEs conduct research on NIH priority pathogens, some of which are agents of
FADs and zoonotic diseases that appear on the OIE lists of animal diseases
and top animal disease threats in the United States (see Tables 2-1 and 2-3 in
Chapter 2).
Most BSL-4 facilities have a common design that couples dedicated in vitro
laboratories with adjacent animal rooms, almost always augmented by dedicated
rooms for necropsy or animal manipulation. Animal rooms are usually about
200-350 ft2 each and are designed to hold rodents, rabbits, or other small ani-
mals in racks; each animal room typically can hold two or more racks. The
rooms may also hold nonhuman primates, which are often housed in racks of
four individual cages (two up, two down), and a single animal room typically
can hold 16 or more nonhuman primates. Widely available modern isolation
units isolate individual cages and limit air mixing between cages of many
smaller laboratory animals, so it is possible to undertake concurrent experiments
with different pathogens by using separate animal cages in the same room
“Biobubbles” or “biorooms” can serve the same purpose for nonhuman primates
but are less commonly used. Animal rooms used to house nonhuman primates
are usually equipped with floor or trench drains with strainers to separate solid
waste. They discharge to a central set of reservoirs where waste is sterilized be-
fore being discharged into the local sewage system. Floor drains may or may not
be in place for animal rooms designed to hold rodents or other small animals.
All solid waste and animal carcasses are sterilized (autoclaved) before leav-
ing the biocontainment laboratory and then usually incinerated. Few of these
facilities have large “digesters” capable of processing experimentally infected
larger animals. Movement of laboratory animals into biocontainment laborato-
ries often involves the use of elevators and passage through open hallways and
loading docks. Waste, animal cages, and bedding are sterilized in double-door
autoclaves as the material leaves the laboratory. Equipment and other imple-
ments can also be decontaminated in an air lock in which a gas (formaldehyde)
or vapor (hydrogen peroxide) is used to fumigate the items. Materials that have
been autoclaved or fumigated are then usually cleaned and prepared for reuse at
a central facility, often in the laboratory complex.
The handling of agriculturally important animals in existing BSL-4 facilities
is challenging but not impossible, although no such facility in the United States
is designated as ABSL-4 for large animals. Some facilities are exploring the use
of miniature goats or pigs for experimental infection with agriculturally impor-
tant BSL-4 pathogens, such as Crimean-Congo hemorrhagic fever, Nipah, and
Hendra viruses. There are many challenges in conducting such experiments,
OCR for page 57
AN INTEGRATED NATIONAL SYSTEM FOR ADDRESSING DISEASES 57
including movement of animals from the supplier into the biocontainment labo-
ratory, animal husbandry and waste management during experimentation, ma-
nipulation of large animals in the BSL-4 environment, necropsy procedures, and
decontamination of animal carcasses after experimental infection. Those chal-
lenges are more fully discussed below.
Choice of Animals
Miniature goats, pigs, young lambs, and perhaps miniature horses could be
used for experimental infections in existing BSL-4 facilities in the United States.
Larger animals, such as horses and cattle, would present major hurdles and are
probably not practical apart from true emergency conditions. The number of
individual animals able to be tested at a given time will be small, and this could
make it difficult to demonstrate statistically significant results. Special equip-
ment for safe handling of any large animals would have to be procured and in-
stalled.
Delivery of Animals
Many existing BSL-4 laboratories are not on the ground level of the build-
ings that house them. Therefore, animals would need to be moved from a trans-
port vehicle to a biocontainment facility by using existing delivery docks, hall-
ways, and elevators that were not designed for movement of large animals. That
problem could be overcome by using crates or other containers for some species
and restricting access while animals are being moved.
Animal Husbandry
Animal husbandry is likely to be one of the most challenging aspects of the
use of domestic animals in existing biocontainment facilities. Special flooring
will be needed to allow efficient waste removal and to provide adequate footing
for and protection of hoofed animals. Individual corrals can be purchased and
installed, or animals can be group-housed in a designated portion of an animal
room. Special arrangements will be required for feed and water.
Monitoring Animals
Individual animals can be monitored for vital signs, such as body tempera-
ture, with implanted sensors and telemetry. However, direct handling of individ-
ual animals for inoculation or to obtain periodic blood samples or other speci-
mens would require the installation of appropriate constraint devices and their
use by trained personnel to facilitate the safe handling of the animals during
such manipulations.
OCR for page 58
58 CRITICAL LABORATORY NEEDS FOR ANIMAL AGRICULTURE
Necropsy and Carcass Disposal
Most necropsy facilities that are now in place are designed to handle labora-
tory animals that are the size of nonhuman primates or smaller. Special adapta-
tions might be required to process larger animals, and preparation of carcasses to
ensure sterilization on completion of studies will be difficult. Disposal of larger
animals after sterilization would require specialized large incinerators that may
not be locally available.
Institutional Oversight
All animal experimentation must be reviewed and approved by an institu-
tional animal care and use committee, and the handling of dangerous pathogens
must be cleared by an institutional biosafety committee. Those committees en-
sure that work to be done meets all existing national standards and that it can be
accomplished safely and securely. In most instances, the institutions will not
have had experience in handling large livestock species, particularly those being
experimentally infected with infectious agents. Convincing the committees that
domestic animals can be manipulated safely and securely under humane condi-
tions in facilities adapted to accommodate large animals will require careful
planning, effective leadership, and a strong partnership between the scientific
investigators and the laboratory animal resources team.
International Resources
BSL-4 laboratories outside the United States that have the capacity to han-
dle large animals are shown in Table 3-2. Each facility has the ability to handle
large domestic animals and some of these laboratories have experience working
with agents that are not currently in the United States but are of research interest
and could be newly introduced into the country (for example, Hendra and Nipah
viruses at the Australian Animal Health Laboratory in Geelong). Depending on
the situation when a request is made, they may be willing to collaborate with US
scientists to investigate pathogens that require BSL-4 containment. Their pri-
mary responsibility is, of course, to their own national governments and domes-
tic needs.
National and international resources and biocontainment infrastructure for
addressing the threat of FADs and zoonotic diseases have expanded substan-
tially since 2001. A discussion of some of the requirements and challenges asso-
ciated with the design and construction of international high-containment labo-
ratories may be found in the report entitled Biosecurity Challenges of the Global
Expansion of High-Containment Biological Laboratories (NAS and NRC, 2012).
Can components of the ideal system for countering disease threats use these
existing resources effectively? The answer is a cautious yes. However, the chal-
OCR for page 59
AN INTEGRATED NATIONAL SYSTEM FOR ADDRESSING DISEASES 59
lenges in using the highest level of biocontainment space (ABSL-4), particularly
for large-animal research and diagnostic development, are not insignificant.
Adaptability and Flexibility for the Future
Technology
Diagnostics, detection, vaccine development, and therapeutics are primary
research necessities to maintain US agricultural strength. The scientific and
technological needs of the diagnostic and response capability of the United
States were outlined in the 2003 National Research Council report Countering
Agricultural Bioterrorism:
“There are needs and opportunities for aggressive research in both science
and technology to improve our ability to prevent, detect, respond to and re-
cover from biological attacks on agricultural plants and animals. The scien-
tific knowledge and the technological developments for protecting plants
and animals against naturally occurring or accidentally introduced pests and
pathogens constitute a starting point for these efforts—but only a starting
point—and there is much more to be done” (p. 67, NRC, 2003).
Knowledge of naturally occurring agents is itself limited, and the landscape
is complicated if one considers intentional introduction of existing or novel
“synthetic” threat agents. Identification and characterization of existing patho-
gens continue to accumulate at rates that are increasing dramatically as a result
of new technologies, such as next-generation sequencing. In general, diagnostic
tests are moving away from antibody-based, single-pathogen laboratory assays
toward nucleic acid-based, multiple-pathogen point-of-care tests. None have yet
been considered fit for the purpose of diagnosing FADs of livestock (whose
prevalence is virtually zero). However, a survey of recent developments in bio-
technology suggests that new, effective methods for diagnosing and tracking
human diseases are available or on the near horizon, application to companion-
animal diseases has already occurred, and further development for diseases of
livestock will follow.
Nanotechnology and microfluidics have contributed to the burgeoning of
detection technologies. For example, several advances in nucleic acid-based
detection devices will allow diagnosis of known infections—even of infection
with BSL-3 organisms—in the field or in the local laboratory. Many of the new
devices, such as lateral-flow (hand-held or dipstick) assays for using both nu-
cleic acid and immunoassays, lead to complete independence from laboratory
instrumentation. Novel variations on the original PCR assay include (among
many) loop-mediated isothermal amplification, molecular beacons, multiplexed
OCR for page 60
60 CRITICAL LABORATORY NEEDS FOR ANIMAL AGRICULTURE
assays, twisted intercalating nucleic acid stabilizing molecules, and dA-tail cap-
turing. Simultaneous interrogation of multiple sequences representing multiple
bacterial and viral pathogens is provided by such systems as “lab-on-a-chip”
designs and DNA-RNA microarrays; originally requiring laboratory access,
these multiplex approaches have recently been adapted to lateral-flow platforms
for field use.
Nucleic acid-based and antibody-based platforms are most widespread, but
direct chemical analysis of organisms with matrix-assisted laser desorption-
ionization time of flight mass spectrometry is also possible. Identification is
based on protein profiles of bacterial pathogens, viral glycoproteins, or even
multiplexed PCR products. Microorganism-based biosensing methods—such as
optical, surface plasmon resonance, amperometric, potentiometric, whole-cell,
electrochemical, impedimetric, and piezoelectric methods—are being adapted
from food-based assays to clinical use.
Despite substantial advances in detection specificity and sensitivity, there is
the remaining problem of sample concentration, as discussed above. Early stages
of infectious diseases may have few organisms in accessible tissues. For exam-
ple, early in Bacillus anthracis infection, few bacteria are in the bloodstream
despite rapid replication because the bacteria are transported into the lymph
nodes by dendritic cells (a subset of immune cells involved in early responses to
infection) and are not accessible in traditional tissue sampling. By the time a
suitable number of bacteria are present for diagnosis, the infection is rampant
and usually fatal. Among the solutions to the problem are detection systems that
have highly effective concentration methods that have been developed for such
diseases as tuberculosis and malaria. Those systems (such as GeneXpert and
DetermineTM TB-LAM) rely on automation of complex, time-consuming proce-
dures and encase an entire process in sealed cartridges with excellent safety re-
cords and reduce the time needed to confirm a diagnosis with high specificity
and sensitivity.
Finally, exponential increases in technology innovation are fueled by in-
tense competition among companies and countries that have marked effects on
research and development. Figure 3-4 shows the rates of performance improve-
ment in two sets of technologies: recombinant DNA and synthetic biology (in-
cluding rapid and low-cost DNA sequencing) (Aldrich et al., 2007). For exam-
ple, revolutionary advances in DNA sequencing methods (next-generation, deep,
and massively parallel sequencing) herald a time when tissue samples from in-
fected animals can be subjected to genome sequencing even without the need for
isolation of the organism. As of May 13, 2012, the complete DNA sequences of
11,681 prokaryotes and 3,097 viruses had been posted,11 and cost and time for
sequencing are decreasing at an unprecedented rate; third-generation (single-
molecule) sequencing will undoubtedly further revolutionize the field.
11
URL: http://www.ncbi.nlm.nih.gov/genome/browse/ (accessed May 12, 2012).
OCR for page 61
AN INTEGRATED NATIONAL SYSTEM FOR ADDRESSING DISEASES 61
FIGURE 3-4 Rates of performance improvement of recombinant-DNA technology and
synthetic biology. SOURCE: Aldrich et al. (2007). Reprinted with permission from Bio
Economic Research Associates, LLC (bio-era™). All rights reserved.
High biocontainment will be required in the near term for development,
testing and validation of some of those approaches. Eventually, their application
to plant and animal health will reduce, but not eliminate, the requirement for
specialized laboratory space.
50-Year Lifespan of the Facility
With forethought and proper planning, the design of a facility with a life-
span of 50 years would take into account changes that might take place during
the life of the building. They include changes in policy, research priorities, tech-
nological developments, societal norms, and global interactions. For example, as
noted above, technological advances will shorten the time to diagnosis and ex-
pand the array of infections detectable with point-of-care or pen-side assays and
reduce laboratory-based testing. Single catastrophic events, such as a massive
outbreak or a terrorist event, can change the landscape of a research field and its
associated policies.
The decade after the 9/11 and 2001 anthrax attacks in the United States saw
unprecedented changes in the regulatory and oversight environment for bio-
medical research in the United States. The confluence of those two events had
substantial effects on laboratory security and safety procedures that limited ac-
cess to dangerous pathogens and altered research priorities. Similar increased
awareness of security and safety issues has occurred on a global level. The new
regulatory environment—on both the national and the international levels—is
subject to constant adjustment and adaptation, and therefore would require that
greater emphasis be placed on the harmonization of regulations: future national
OCR for page 62
62 CRITICAL LABORATORY NEEDS FOR ANIMAL AGRICULTURE
animal agricultural infrastructure and policies would need to be planned with the
potential for these changes in mind.
Similarly, societal values and public attitudes related to the welfare of agri-
cultural animals continue to evolve (Blokhuis et al., 2008). Organizations such
as OIE are actively promoting the importance of integrating animal health, ani-
mal welfare, and food safety. Although the United States currently does not leg-
islate food animal welfare,12 the European Commission recently adopted a new
4-year strategy (2012-2015) to improve the welfare of animals in the European
Union.13
Research and development in animal protection will require BSL-3Ag and
ABSL-4 for decades to come. Researchers will need to understand disease
pathogenesis to develop efficient detection and diagnostic methods or new vac-
cines. For example, some animals immunized with inactivated foot-and-mouth
disease vaccines are still capable of maintaining persistent infection (Kitching,
2002). The variability of foot-and-mouth disease serotypes restricts the use of
existing vaccine stocks in an outbreak until a full epidemiological characteriza-
tion has been carried out and studies to determine whether the vaccine will pro-
vide sufficient immunity against the viral outbreak strain have been conducted
(Rodriguez and Gay, 2011). Furthermore, if vaccines are used to control an out-
break, the ability to detect infection in vaccinated animals and to differentiate
between infected and immunized animals is required if animal products are to be
moved within the country and globally. As more is understood about disease
progression and virulence determinants in infection, attenuated or recombinant
viral vaccines will be produced by using reverse-engineering and other synthetic
technologies, with serotype specificity and DIVA properties. Development of
such a vaccine is well advanced in the United States and abroad. Those and
other novel vaccine-production platforms are essential for rapid response to
foot-and-mouth disease outbreaks and will need to be tested in large animals in
strict containment. The committee notes that one such foot-and-mouth disease
vaccine was licensed recently (June 2012). This vaccine was a product of PIADC
and USDA-ARS research in cooperation with DHS and the private sector.14
Vaccine development for agents that are emerging as high-priority disease
threats may also require high biocontainment. Bunyaviruses, such as Crimean-
Congo hemorrhagic fever virus and Rift Valley fever virus, are the causative
agents of devastating diseases and have an expanding host and geographic
range. Investigation of those agents in livestock species is necessary. Recent
advances in research methods such as infectious-virus rescue, novel electron
microscopic techniques, and high-resolution structural analysis have been ap-
12
See URL: http://awic.nal.usda.gov/farm-animals/animal-welfare-audits-and-certifica
tion-programs (accessed May 31, 2012).
13
See URL: http://ec.europa.eu/food/animal/welfare/actionplan/actionplan_en.htm.
(accessed May 31, 2012).
14
See URL: http://www.prnewswire.com/news-releases/genvec-announces-conditiona
l-approval-of-fmd-vaccine-for-cattle-157766595.html (accessed June 29, 2012).
OCR for page 63
AN INTEGRATED NATIONAL SYSTEM FOR ADDRESSING DISEASES 63
plied to both emerging bunyaviruses and model species (Walter and Barr, 2011).
The study of those agents has high priority in view of the lack of vaccines and
therapeutics for their treatment and control and requires high biocontainment.
Finally, the committee also recognizes that there are international research
efforts to develop vaccination studies that involve no challenge infections of
animals with live virus. These studies are critical for the large number of coun-
tries recognized by the OIE as “foot-and-mouth disease-free with vaccination”
whose foot-and-mouth disease research facilities are unable to use live FMDv
for any studies or challenges. Efficacy studies for FMDv would be based solely
on the evaluation of immune response elicited by vaccination, as is already hap-
pening in the case of foot-and-mouth disease vaccines manufactured in South
America under guidelines of the Pan-American Foot-and-Mouth Disease Center
(PANAFTOSA). It is expected that efforts to develop alternative efficacy stud-
ies of new vaccines without experimental challenge infections of live animals
will continue to evolve given regulatory and societal pressures to limit the num-
ber of animals used in infectious disease research, with an obvious impact on the
capacity needed for animal studies in high biocontainment.
SUMMARY
Despite the marked expansion of high-biocontainment space in the United
States since 2001, there remains no national ABSL-4 large-animal facility. Simi-
larly, although BSL-3Ag containment space has expanded through construction
of several new facilities (for example, the Biosecurity Research Institute and the
National Animal Disease Center), the facilities at PIADC dedicated to FADs are
dated and increasingly cost-inefficient. Thus, there is a critical national need for
a dedicated facility that has modern BSL-3Ag and ABSL-4 large-animal capa-
bilities. It would serve as the hub of the national strategy for the detection of and
response to any incursion of an FAD. It would also be used for the study of in-
fectious diseases of public-health importance in which livestock serve as key
reservoir or amplifying hosts.
US programs for detection of and response to FADs (those proposed to be
located at the NBAF) would need to interface with similar activities and pro-
grams of the National Biodefense Analysis and Countermeasures Center, the
Centers for Disease Control and Prevention, the US Army Medical Research
Institute for Infectious Diseases, USDA, NIH, and academic and state institu-
tions to maximize efficiency and intellectual resources through interdisciplinary
research that crosses traditional agency boundaries. Such interagency working
relationships may have challenges, but would be essential for maximizing the
use of the NBAF as well as other existing BSL-3Ag, BSL-4 and ABSL-4 labora-
tories in the United States and the skilled workforce they employ. The rapidly
evolving nature of disease threats confronting the animal industries of the
United States and the technologies available to detect and respond to them de-
mand a flexible and nimble strategy for programmatic and facility design. With
OCR for page 64
64 CRITICAL LABORATORY NEEDS FOR ANIMAL AGRICULTURE
that background, in Chapter 4 the committee considers in more detail the three
options presented in its statement of task: constructing the NBAF as currently
designed, scaling back the size and scope of the proposed NBAF, and maintain-
ing the current PIADC and leveraging US capability and capacity through inter-
national laboratories that have ABSL-4 large-animal space.
REFERENCES
Aldrich, S.C., J. Newcomb, and R. Carlson. 2007. Figure 1-2. An inflection point for
biological technology . In Genome Synthesis and Design Futures: Implications for
the US Economy. Bio-era.net [online]. Available: http://www.bio-era.net/reports/
genome.html (accessed June 5, 2012).
Baker, M.G., and D.P. Fidler. 2006. Global public health surveillance under new interna-
tional health regulations. Emerging Infectious Disease 12(7):1058-1065.
Berns, K.I., A. Casadevall, M.L. Cohen, S. Ehrlich, L.W. Enquist, J.P. Fitch, D.R. Franz,
C.M. Fraser-Liggett, C.M. Grant, M.J. Imperiale, J. Kanabrocki, P.S. Keim, S.M.
Lemon, S.B. Levy, J.R. Lumpkin, J.F. Miller, R. Murch, M.E. Nance, M.T. Oster-
holm, D.A. Relman, J.A. Roth, and A. Vidaver. 2012. Adaptations of avian flu virus
are a cause for concern. Science 335(6069):660-661.
Blokhuis, H.J., L.J. Keeling, A. Gavinelli, and J. Serratosa. 2008. Animal welfare’s im-
pact on the food chain. Trends in Food Science and Technology 19 (suppl. 1):S79-
S87.
Brownlie, J., C. Peckham, J. Waage, M. Woolhouse, C. Lyall, L. Meagher, J. Tait, M. Bay-
lis, and A. Nicoll. 2006. Foresight. Infectious Diseases: Preparing for the Future. Fu-
ture Threats. London: Office of Science and Innovation [online]. Available:
http://www.bis.gov.uk/assets/foresight/docs/infectious-diseases/t1.pdf (accessed June
4, 2012).
CDC (Centers for Disease Control and Prevention). 2009. Biosafety in Microbiological and
Biomedical Laboratories (BMBL), 5th Ed. (CDC) 21-1112. [online]. Available: http://
www.cdc.gov/biosafety/publications/bmbl5/BMBL.pdf (accessed June 5, 2012).
CNA. 2011. Enhancing Ag Resiliency: The Agricultural Industry Perspective of Utilizing
Agricultural Screening Tools. Report from the Agricultural Screening Tools Work-
shop, April 2011, Washington D.C. College Station, TX: National Center for For-
eign Animal and Zoonotic Disease Defense, Texas A&M University [online]. Avail-
able; http://fazd.tamu.edu/files/2011/06/ASTII-Report-FINAL.pdf (accessed June 5,
2012).
Enserink, M., and J. Cohen. 2012. One H5N1 paper finally goes to press; Second
greenlighted. Science 336(6081):529-530.
Fidler, D.P. 2005. From international sanitary conventions to global health security: The
new international health regulations. Chinese Journal of International Law 4(2):325-
392.
IOM (Institute of Medicine). 2003. Microbial Threats to Health: Emergence, Detection,
and Response. M.S. Smolinski, M. A. Hamburg, and J. Lederberg, eds. Washington,
DC: The National Academies Press.
IOM and NRC (National Research Council). 2009. Sustaining Global Surveillance and
Response to Emerging Zoonotic Diseases. G.T. Keusch, M. Pappaioanou, M.C.
Gonzalez, K.A. Scott, and P. Tsai, eds. Washington, DC: The National Academies
Press.
OCR for page 65
AN INTEGRATED NATIONAL SYSTEM FOR ADDRESSING DISEASES 65
Kahn, C.M., and S. Line, eds. 2011. Akabane virus infection. The Merck Veterinary
Manual. Whitehouse Station, NJ: Merck [online]. Available: http://www.merck
vetmanual.com/mvm/index.jsp?cfile=htm/bc/50804.htm (accessed June 29, 2012).
Kitching, R.P. 2002. Identification of foot and mouth disease virus carrier and subclini-
cally infected animals and differentiation from vaccinated animals. Scientific and
Technical Review 21(3):531-538.
NAS (National Academy of Sciences) and NRC. 2012. Biosecurity Challenges of the
Global Expansion of High-Containment Biological Laboratories: Summary of a
Workshop. Washington, DC: The National Academies Press.
NASDARF (The National Association of State Departments of Agriculture Research
Foundation). 2001. The Animal Health Safeguarding Review: Results and Recom-
mendations, October 2001 [online]. Available: http://www.aphis.usda.gov/vs/pdf_
files/safeguarding.pdf (accessed June 8, 2012).
NRC (National Research Council). 2003. Countering Agricultural Bioterrorism. Wash-
ington, DC: The National Academies Press.
OIE (World Organization for Animal Health). 2010. Chapter 1.2 Criteria for Listing Dis-
eases Article 1.2.1. Terrestrial Animal Health Code 2010 [online]. Available:
http://web.oie.int/eng/normes/mcode/en_chapitre_1.1.2.pdf (accessed June 1, 2012).
Rodriguez, L.L., and C.G. Gay. 2011. Development of vaccines toward the global control
and eradication of foot-and-mouth disease. Expert Review of Vaccines 10(3):377-
387.
USDA (US Department of Agriculture). 2012. USDA Responses and Supporting Materi-
als to the Questions Sent by the Committee. April 27, 2012.
USDA-APHIS (US Department of Agriculture, Animal and Plant Health Inspection Ser-
vice). 2012. National Animal Health Laboratory Network (NAHLN) [online].
Available: http://www.aphis.usda.gov/animal_health/nahln/content/wp_c_map_disp.
php?lab=all_labs_disease_designations (accessed June 5, 2012).
Walter, C.T., and J.N. Barr. 2011. Recent advances in the molecular and cellular biology
of bunyaviruses. Journal of General Virology 92:2467-2484.
WHO (World Health Organization). 2007. International Health Regulations (2005): Ar-
eas of Work for Implementation. WHO/CDS/EPR/IHR/2007.1. France, Lyon:
World Health Organization [online]. Available: http://www.who.int/ihr/finalversion
9Nov07.pdf (accessed June 4, 2012).
OCR for page 66
